Abstract
Recent efforts in the field of carbohydrate chemistry have focused on the site- and stereocontrolled synthesis of O-glycosides derived from acceptors bearing multiple hydroxyl substituents. By comparison, there are few examples of the site-selective synthesis of O-glycosides bearing free hydroxyl substituents on the donor reagent. Here, we report the application of an umpolung glycosylation strategy to the synthesis of O-glycosides derived from donors bearing free hydroxyl substituents. The reaction proceeds via prior deprotonation of one or more free hydroxyl groups on a thiophenylglycoside donor, reductive lithiation to generate an anomeric anion intermediate, and addition of this anion to an alkyl 2-(2-methyltetrahydropyranyl) peroxide. By this approach, α-linked glycosides were obtained in 39-84% yields and with >50:1 α/β selectivities. In many instances, β-linked products could be obtained by thermal equilibration of the anomeric anion intermediate (selectivities = 3.8-8:1 β/α; yields = 33-68%). The strategy is applicable to polyhydroxyl donors bearing up to three free hydroxyl groups, N-acylated carbohydrates, and the single-flask syntheses of oligosaccharides.